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In chronic pulmonary sarcoidosis, the transition from the inflammatory to the fibrotic stage of the lungs occurs in about 10-20% of cases, eventually causing end-stage fibrotic disease. To date, pathogenetic mechanisms and clinical management remain challenging; thus, we highlight the recent evidence in pulmonary fibrotic processes, clinical signs for an early detection and the potential role of the current investigated antifibrotic agents and promising targeted therapies.Recent findings of relevant key cellular pathways can be considered as a glimmer of light in the complexity of sarcoidosis. In some patients, granulomas persist and serve as a nidus for fibrosis growth, sustained by several fibrosis-stimulating cytokines. Preclinical studies have detected profibrotic, antifibrotic and pleiotropic T cells as promoters of fibrosis. Epigenetics, genetics and transcriptomics research can lead to new target therapies. Antifibrotic drug nintedanib has shown a positive effect on non-idiopathic pulmonary fibrosis fibrotic lung diseases including fibrotic sarcoidosis; other antifibrotic drugs are under investigation.Pulmonary fibrosis strongly impacts the outcome of sarcoidosis, and a better understanding of the underlying pathogenic mechanisms can facilitate the development of novel treatments, improving clinical care and life expectancy of these patients. The greatest challenge is to investigate effective antifibrotic therapies once fibrosis develops. The role of these findings in fibrotic sarcoidosis can be translated into other interstitial lung diseases characterized by the coexistence of inflammatory and fibrotic processes.

In 2020, COPD was the third leading cause of death worldwide. Lung function is central for the diagnosis of this disease, and COPD severity is still partially classified based on airflow obstruction, which can range from “mild” (GOLD 1 group, FEV1 ≥80% predicted) to “very severe” (GOLD 4, FEV1

Prone positioning is frequently used for non-intubated hypoxemic patients with COVID-19, although conclusive evidence is still lacking. The aim of the present study was to investigate whether baseline CT-scans could predict the improvement in oxygenation in COVID-19 related Acute respira-tory syndrome (ARDS) patients when pronated. Methods: A retrospective study of COVID-19 patients who underwent non-invasive ventilation (NIV) and prone positioning was conducted. Results: Forty-five patients were included. On average, 50% of the overall lung volume was affected by the disease, as observed in the CT-scans, with ground glass opacities (GGOs) and consolidations accounting for 44% and 4%, respectively. The abnormalities were mainly posterior, as demonstrated by posterior/anterior distribution ratios of 1.5 and 4.4 for GGO and consolidation, respectively. The median PaO2/FiO2 ratio during NIV in a supine position (SP1) was 140 [IQR 108–169], which improved by 67% (+98) during prone positioning, on average. Once supine positioning was resumed (SP2), the improvement in oxygenation was maintained in 28 patients (62% of the overall population, categorized as “responders”). We found no significant differences between responders and non-responders in terms of the extent (p = 0.92) and the distribution of parenchymal abnormalities seen in the baseline CT (p = 0.526). Conclusion: Despite the lack of a priori estimation of the sample size, considering the absence of any trends in the differences and correlations, we can reasonably conclude that the baseline chest CT-scan does not predict a gas-exchange response in awake prone-positioned patients with COVID-19 related ARDS. Physicians dealing with this category of patients should not rely on the imaging at presentation when evaluating whether to pronate patients.

Background Sarcopenia gained importance in the evaluation of patients with chronic respiratory diseases, including idiopathic pulmonary fibrosis (IPF), since it may impact negatively on clinical outcomes. Aim Aim of this study is to evaluate the prevalence and factors associated with sarcopenia, defined according to the European Working Group on Sarcopenia in Older People 2 (EWGSOP2) 2019 definition, and to evaluate the prevalence of the single criteria that define the EWGSOP2 definition (muscle strength, muscle quantity and physical performance), in a cohort of consecutive patients with IPF prospectively followed up in 9 hospitals in Northern Italy between December 2018 and May 2021. Methods Enrolled patients underwent an extensive pulmonary and nutritional assessment, including bioelectrical impedance analysis, dynamometry and 4-m gait speed test, both at IPF diagnosis and at 6-month follow-up. Results Out of the 83 patients (81% males, mean age 72.5 years) with IPF at disease diagnosis enrolled in the study, 19 (22.9%) showed sarcopenia, including 2 (2.4%) with severe sarcopenia, 5 (6.0%) with confirmed sarcopenia and 12 (14.5%) with probable sarcopenia. Sarcopenia was associated with a significantly higher severity of the disease and sedentary lifestyle, while no differences were observed in regards to body mass index, history of weight loss and comorbidities between patients with and without sarcopenia. Out of the 64 patients without sarcopenia at baseline, 16 cases showed alteration of muscle quantity and/or physical performance. In the 51 patients with complete data at 6-month follow-up, there were no cases of severe sarcopenia, 1 case (2.0%) showed confirmed sarcopenia, while the prevalence of probable sarcopenia was 19.6% (10 cases). No differences in regards to antifibrotic treatment received and onset of gastrointestinal side effects were observed between patients with and without sarcopenia at follow-up. Conclusions The prevalence of sarcopenia in patients with IPF both at diagnosis and at 6-month follow-up was low but not negligible and was associated with higher severity of the disease and sedentary lifestyle. In IPF patients, a comprehensive diagnostic work-up including all the criteria defining the EWGSOP2 definition might be more useful than a series testing for prompt recognition of nutritional and physical performance abnormalities.

BACKGROUND Phosphodiesterase 4 (PDE4) inhibition is associated with antiinflammatory and antifibrotic effects that may be beneficial in patients with idiopathic pulmonary fibrosis. METHODS In this phase 2, double-blind, placebo-controlled trial, we investigated the efficacy and safety of BI 1015550, an oral preferential inhibitor of the PDE4B subtype, in patients with idiopathic pulmonary fibrosis. Patients were randomly assigned in a 2:1 ratio to receive BI 1015550 at a dose of 18 mg twice daily or placebo. The primary end point was the change from baseline in the forced vital capacity (FVC) at 12 weeks, which we analyzed with a Bayesian approach separately according to background nonuse or use of an antifibrotic agent. RESULTS A total of 147 patients were randomly assigned to receive BI 1015550 or placebo. Among patients without background antifibrotic use, the median change in the FVC was 5.7 ml (95% credible interval, -39.1 to 50.5) in the BI 1015550 group and -81.7 ml (95% credible interval, -133.5 to -44.8) in the placebo group (median difference, 88.4 ml; 95% credible interval, 29.5 to 154.2; probability that BI 1015550 was superior to placebo, 0.998). Among patients with background antifibrotic use, the median change in the FVC was 2.7 ml (95% credible interval, -32.8 to 38.2) in the BI 1015550 group and -59.2 ml (95% credible interval, -111.8 to -17.9) in the placebo group (median difference, 62.4 ml; 95% credible interval, 6.3 to 125.5; probability that BI 1015550 was superior to placebo, 0.986). A mixed model with repeated measures analysis provided results that were consistent with those of the Bayesian analysis. The most frequent adverse event was diarrhea. A total of 13 patients discontinued BI 1015550 treatment owing to adverse events. The percentages of patients with serious adverse events or severe adverse events were similar in the two trial groups. CONCLUSIONS In this placebo-controlled trial, treatment with BI 1015550, either alone or with background use of an antifibrotic agent, prevented a decrease in lung function in patients with idiopathic pulmonary fibrosis. (Funded by Boehringer Ingelheim; 1305-0013 ClinicalTrials.gov number, NCT04419506.)

The enthusiasm generated by the approval of pirfenidone and nintedanib as the first effective therapies for IPF led the IPF scientific community to investigate an increasing number of novel agents in well-designed randomized controlled trials, in the hope to find a cure for these patients.This reviews the evidence from IPF phase II trials that were completed or started in 2020. Literature search was performed using Medline and Clinicaltrials.org databases.Randomized clinical trials revolutionized the management of IPF, leading to the discovery of the first therapies capable of slowing down functional deterioration in these patients. The recently published findings of the first successful phase II trials since pirfenidone and nintedanib will hopefully inaugurate a new era in the therapeutic scenario of IPF, where consolidated treatments of proven efficacy and novel targeted agents contribute together to reach the final goal of halting the fibrotic process of this dreadful disease.

Severe asthma is burdened by frequent exacerbations and use of oral corticosteroids (OCS), which worsen patients’ health and increase healthcare spending. The aim of this study was to assess the clinical and economic impact of switching from omalizumab (OMA) to mepolizumab (MEP) in patients eligible for both biologics, but not optimally controlled by omalizumab. We retrospectively enrolled uncontrolled severe asthmatic patients who switched from OMA to MEP during the last two years. Information included blood eosinophil count, asthma control test (ACT), spirometry, serum IgE, fractional exhaled nitric oxide (FeNO), OCS intake, drugs, exacerbations/hospitalizations, visits and diagnostic exams. Within the perspective of Italian National Health System, a pre- and post-MEP 12-month standardized total cost per patient was calculated. 33 patients were enrolled: five males, mean age 57 years, disease onset 24 years. At OMA discontinuation, 88% were OCS-dependent with annual mean rate of 4.0 clinically significant exacerbations, 0.30 exacerbations needing emergency room visits or hospitalization; absenteeism due to disease was 10.4 days per patient. Switch to MEP improved all clinical outcomes, reducing total exacerbation rate (RR = 0.06, 95% CI 0.03–0.14), OCS-dependent patients (OR = 0.02, 95% CI 0.005–0.08), and number of lost working days (Δ = − 7.9, 95% CI − 11.2 to − 4.6). Pulmonary function improved, serum IgE, FeNO and eosinophils decreased. Mean annual costs were €12,239 for OMA and €12,639 for MEP (Δ = €400, 95% CI − 1588–2389); the increment due to drug therapy (+ €1,581) was almost offset by savings regarding all other cost items (− €1,181). Patients with severe eosinophilic asthma, not controlled by OMA, experienced comprehensive benefits by switching to MEP with only slight increases in economic costs.

Background In the INBUILD trial in patients with chronic fibrosing interstitial lung diseases (ILDs) and a progressive phenotype, nintedanib reduced the rate of ILD progression with adverse events that were manageable for most patients. We investigated the potential impact of immunomodulatory therapies on the efficacy and safety of nintedanib. Methods Subjects with fibrosing ILDs other than idiopathic pulmonary fibrosis, who had shown progression of ILD within the prior 24 months despite management in clinical practice, were randomized to receive nintedanib or placebo. Certain immunomodulatory therapies were restricted for the first 6 months. We analyzed post-hoc the rate of decline in forced vital capacity (FVC) over 52 weeks in subgroups by glucocorticoid use at baseline and in analyses excluding subjects or FVC measurements taken after initiation of restricted immunomodulatory or antifibrotic therapies. Results Of 663 subjects, 361 (54.4%) were taking glucocorticoids at baseline (353 at a dose of ≤ 20 mg/day). In the placebo group, the adjusted rate of decline in FVC (mL/year) over 52 weeks was numerically greater in subjects taking than not taking glucocorticoids at baseline (− 206.4 [SE 20.2] vs − 165.8 [21.9]). The difference between the nintedanib and placebo groups was 133.3 (95% CI 76.6, 190.0) mL/year in subjects taking glucocorticoids at baseline and 76.1 (15.0, 137.2) mL/year in subjects who were not (interaction P = 0.18). The effect of nintedanib on reducing the rate of FVC decline in analyses excluding subjects or measurements taken after initiation of restricted immunomodulatory or antifibrotic therapies was similar to the primary analysis. The adverse event profile of nintedanib was similar between subjects who did and did not use prohibited or restricted therapies at baseline or during treatment with trial drug. Conclusions In patients with progressive fibrosing ILDs, the effect of nintedanib on reducing FVC decline was not influenced by the use of immunomodulatory therapies. Nintedanib can be used in combination with immunomodulatory therapies in patients with progressive fibrosing ILDs. Trial registration ClinicalTrials.gov, NCT02999178. Registered 21 December 2016, https://clinicaltrials.gov/ct2/show/NCT02999178

The last two decades witnessed an increasing number of well-designed late phase trials in patients with Idiopathic Pulmonary Fibrosis (IPF), leading to the approval of the first effective therapies...

Luca Richeldi,1 Alessio Piraino,2 Francesco Macagno,1 Gianluigi Micarelli,2 Eleonora Ingrassia2 1Unità Operativa Complessa di Pneumologia, Università Cattolica del Sacro Cuore, Fondazione Policlinico A, Gemelli, Rome; 2Chiesi Italia S.p.a., Parma, ItalyCorrespondence: Gianluigi MicarelliChiesi Italia S.p.a., Via Giacomo Chiesi 1, Parma 43122, ItalyTel +39 345 6350692Fax +39 0521 279592Email g.micarelli@chiesi.comBackground: The fixed triple combination Beclometasone dipropionate/Formoterol fumarate/Glycopyrronium (BDP/FF/G, Trimbow®), an extrafine formulation in a unique pressurized metered dose inhaler, is indicated for the maintenance treatment in adult patients with moderate to severe COPD, not adequately treated by ICS/LABA or LABA/LAMA. Besides the evidence from three randomized controlled trials, the impact of fixed triple therapy has not been extensively evaluated in a real-world population of COPD patients. TRITRIAL (TRIple Therapy in Real life: Impact on Adherence and HeaLth status) is a non-interventional study to assess the effect of BDP/FF/G in a real world setting in Italy.Design: TRITRIAL is a 12-month, multicenter, cohort, prospective, longitudinal observational study. Two follow-up visits will be performed at 6 and 12 months, respectively. The study includes the collection of anamnestic clinical and functional data before the start of BDP/FF/G. The study is built for digital conduction, from signature of the informed consent on a dedicated web platform, to the collection of questionnaires and clinical data on the eCRF.Population: A total of 800 patients with COPD ranging from Global Initiative for Obstructive Lung Disease (GOLD) stages 2 to 4, receiving therapy with BDP/FF/G according to the Summary of Product Characteristics and local clinical practice, will be recruited. All concomitant therapies will be permitted for the duration of the study.Evaluations: The primary endpoint is the change of CAT score at 12 months versus baseline. Secondary endpoints are adherence, health-related quality of life, sleep quality, disease-related outcomes (lung function and COPD exacerbations), device usability, economic resources consumption, and safety.Conclusion: TRITRIAL study is expected to give relevant information about effectiveness of BDP/FF/G fixed triple therapy in a real-life setting of patients with COPD, where adherence, usability of inhalers and patient’s preference of the device are crucial factors for the success of the therapy.Keywords: COPD, symptoms, health status, adherence, LAMA, LABA, ICS

Senescence is a stress-response process characterized by the irreversible inhibition of cell proliferation, associated to the acquisition of a senescence-associated secretory phenotype (SASP), that may drive pathological conditions. Lymphangioleiomyomatosis (LAM) is a rare disease in which LAM cells, featuring the hyperactivation of the mammalian Target of Rapamycin Complex 1 (mTORC1) for the absence of tuberin expression, cause the disruption of the lung parenchyma. Considering that LAM cells secrete SASP factors and that mTOR is also a driver of senescence, we deepened the contribution of senescence in LAM cell phenotype. We firstly demonstrated that human primary tuberin-deficient LAM cells (LAM/TSC cells) have senescent features depending on mTOR hyperactivation, since their high positivity to SA-β galactosidase and to phospho-histone H2A.X are reduced by inducing tuberin expression and by inhibiting mTOR with rapamycin. Then, we demonstrated the capability of LAM/TSC cells to induce senescence. Indeed, primary lung fibroblasts (PLFs) grown in LAM/TSC conditioned medium increased the positivity to SA-β galactosidase and to phospho-histone H2A.X, as well as p21

While lung ultrasonography (LUS) proved to be a useful diagnostic and prognostic tool in acute phase of COVID 19 pneumonia, its role in detecting long-term pulmonary sequelae has yet to be explored. In our prospective observational study we assessed the potential of LUS in detecting the presence of computed tomography (CT) fibrotic-like changes after 6 months from COVID-19 pneumonia. Patients who were discharged with a diagnosis of severe COVID-19 pneumonia were enrolled. After 6 months from hospital discharge they underwent LUS, chest CT scan and pulmonary function tests. A logistic regression analysis was performed to assess the association between presence of symptoms, LUS score and diffusing capacity for carbon monoxide (DLCO) at 6-month after hospital discharge and CT scan fibrotic-like changes. A second logistic model was performed to assess the value of some predefined baseline factors (age, sex, worst PaO2/FiO2, ventilator support, worst CRP value, worst D-dimer value and worst LUS score during hospitalization) to predict fibrotic-like changes on 6-month CT scan. Seventy-four patients were enrolled in the study. Twenty-four (32%) showed lung abnormalities suitable for fibrotic-like changes. At multivariate logistic regression analysis LUS score after 6 months from acute disease was significantly associated with fibrotic-like pattern on CT scan. The second logistic model showed that D-dimer value was the only baseline predictive variable of fibrotic-like changes at multivariate analysis. LUS performed after 6 months from severe COVID-19 pneumonia may be a promising tool for detection and follow-up of pulmonary fibrotic sequelae.

Etiological diagnosis of mediastinal lymphadenopathy represents a daily challenge. Endosonography (transesophageal and transbronchial ultrasound-guided needle aspiration) is the recommended technique in the first diagnostic work-up and in the mediastinal staging of lung cancer. Despite a good sensitivity, limited amount of collected tissue may hamper molecular assessment in advanced lung cancer and in the diagnosis of lymphoproliferative disorders, fibrotic sarcoidosis, and mycobacterial lymphadenitis. Cryobiopsy, a bronchoscopic technique based on cooling, crystallization, and subsequent collection of tissue, has been successfully employed in the diagnosis of interstitial lung diseases. Cryoprobes provide larger amount of tissue than conventional bronchoscopic sampling tools and might potentially prevent the need for invasive surgical procedures. New applications of the technique (e.g., bronchoscopic diagnosis of peripheral pulmonary lesions and mediastinal lymph nodes) have been recently described in few reports. In a recent issue of the Journal, Genova et al. described five patients who underwent endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) followed by ultrasound-guided transbronchial cryobiopsy of mediastinal lymphadenopathy for a suspected malignancy. The authors discussed about the potential added value of mediastinal cryobiopsy on a correct histopathological and molecular assessment in patients with malignancies. EBUS-cryobiopsy could be a promising technique in the diagnostic pathway of mediastinal lymphadenitis. However, cryobiopsy is now available only in few selected centres. The learning curve of the technique adapted to mediastinal ultrasound-guided sampling, the optimal sampling strategy, its true diagnostic accuracy in patients with malignant and benign diseases, as well as its safety, are still largely unclear. Mediastinal cryobiopsy could be complementary rather than alternative to conventional endosonography. Rapid on-site evaluation of EBUS-TBNA could guide subsequent sampling with cryoprobes in case of poor collection of biological material or in case of suspected lymphoproliferative disorders. Further studies should investigate its diagnostic yield, in comparison or in combination with conventional endosonography, in large cohorts of patients with malignant or benign mediastinal lymphadenopthies.

Non-tuberculous mycobacteria (NTM) are ubiquitous environmental microorganisms capable of a wide range of infections that primarily involve the lymphatic system and the lower respiratory tract. In recent years, cases of lung infection sustained by NTM have been steadily increasing, due mainly to the ageing of the population with underlying lung disease, the enlargement of the cohort of patients undergoing immunosuppressive medications and the improvement in microbiologic diagnostic techniques. However, only a small proportion of individuals at risk ultimately develop the disease due to reasons that are not fully understood. A better understanding of the pathophysiology of NTM pulmonary disease is the key to the development of better diagnostic tools and therapeutic targets for anti-mycobacterial therapy. In this review, we cover the various types of interactions between NTM and lymphoid effectors of innate and adaptive immunity. We also give a brief look into the mechanism of immune exhaustion, a phenomenon of immune dysfunction originally reported for chronic viral infections and cancer, but recently also observed in the setting of mycobacterial diseases. We try to set the scene to postulate that a better knowledge of immune exhaustion can play a crucial role in establishing prognostic/predictive factors and enabling a broader investigation of immune-modulatory drugs in the experimental treatment of NTM pulmonary disease.

Continuous positive airway pressure (CPAP), the first line therapy for obstructive sleep apnea (OSA), is considered effective in reducing daytime sleepiness. Its efficacy relies on adequate adherence, often defined as >4 hours per night. However, this binary threshold may limit our understanding of the causal effect of CPAP adherence and daytime sleepiness and multilevel approach for CPAP adherence can be more appropriate.

Mepolizumab and benralizumab are clinically effective biological treatments for severe eosinophilic asthmatic patients by hampering eosinophilic inflammation. The effects of these compound on the immunoglobulin (Ig)E T2 component are virtually unknown.To evaluate the change in total IgE levels at 4 ± 2 months after initiation of the mepolizumab (primary outcome) or benralizumab. When available, the changes of blood inflammatory cell counts, lung function and asthma control test (ACT) were also assessed and correlated with changes in total IgE levels.Observational, retrospective, multicentre, cohort study. Severe eosinophilic atopic asthmatic patients treated with mepolizumab or benralizumab were included in the analysis.Three-month treatment (on average) with mepolizumab (Benralizumab but not mepolizumab, treatment led to a significant reduction of circulating IgE level. The study provides different and specific mechanisms of action for anti-IL5-pathway treatments.

[No Abstract Available], NIHR Southampton Biomedical Research Centre; Wellcome Trust [209553/Z/17/Z]; NIHR UCLH Biomedical Research Centre, UK, J.M. Wallis receives a research fellowship from the NIHR Southampton Biomedical Research Centre. This research was funded in whole or in part by the Wellcome Trust (209553/Z/17/Z). For this project, J. Jacob and E. Gudmundsson were also supported by the NIHR UCLH Biomedical Research Centre, UK. Funding information for this article has been deposited with the Crossref Funder Registry.

Background: When considering the diagnosis of idiopathic pulmonary fibrosis (IPF), experienced clinicians integrate clinical features that help to differentiate IPF from other fibrosing interstitial lung diseases, thus generating a “pre-test” probability of IPF. The aim of this international working group perspective was to summarize these features using a tabulated approach similar to chest HRCT and histopathologic patterns reported in the international guidelines for the diagnosis of IPF, and to help formally incorporate these clinical likelihoods into diagnostic reasoning to facilitate the diagnosis of IPF. Methods: The committee group identified factors that influence the clinical likelihood of a diagnosis of IPF, which was categorized as a pre-test clinical probability of IPF into “high” (70–100%), “intermediate” (30–70%), or “low” (0–30%). After integration of radiological and histopathological features, the post-test probability of diagnosis was categorized into “definite” (90–100%), “high confidence” (70–89%), “low confidence” (51–69%), or “low” (0–50%) probability of IPF. Findings: A conceptual Bayesian framework was created, integrating the clinical likelihood of IPF (“pre-test probability of IPF”) with the HRCT pattern, the histopathology pattern when available, and/or the pattern of observed disease behavior, into a “post-test probability of IPF.” The diagnostic probability of IPF was expressed using an adapted diagnostic ontology for fibrotic interstitial lung diseases. Interpretation: The present approach will help incorporate the clinical judgment into the diagnosis of IPF, thus facilitating the application of IPF diagnostic guidelines and, ultimately improving diagnostic confidence and reducing the need for invasive diagnostic techniques.

The acceptable duration of donor warm ischemia time (DWIT) after cardiocirculatory death (DCD) is still debated. We analyzed the biomolecular profile and function during ex vivo lung perfusion (EVLP) of DCD lungs and their correlation with lung transplantation (LuTx) outcomes. Donor data, procurement times, recipient outcomes, and graft function up to 1 year after LuTx were collected. During EVLP, the parameters of graft function and metabolism, perfusate samples to quantify inflammation, glycocalyx breakdown products, coagulation, and endothelial activation markers were obtained. Data were compared to a cohort of extended-criteria donors after brain death (EC-DBD). Eight DBD and seven DCD grafts transplanted after EVLP were analyzed. DCD's DWIT was 201 [188;247] minutes. Donors differed only regarding the duration of mechanical ventilation that was longer in the EC-DBD group. No difference was observed in lung graft function during EVLP. At reperfusion, "wash-out" of inflammatory cells and microthrombi was predominant in DCD grafts. Perfusate biomolecular profile demonstrated marked endothelial activation, characterized by the presence of inflammatory mediators and glycocalyx breakdown products both in DCD and EC-DBD grafts. Early graft function after LuTx was similar between DCD and EC-DBD. DCD lungs exposed to prolonged DWIT represent a potential resource for donation if properly preserved and evaluated.

Idiopathic pulmonary fibrosis (IPF) is a devastating progressive fibrotic disease affecting the lungs and causing chronic respiratory failure. In IPF, adult alveolar type II stem cells (ATII) cannot trans-differentiate to alveolar type I cells (ATI), and therefore, represents a relevant target in the progression of lung fibrosis. There are only two FDA-approved drugs for the treatment of IPF, which can only ameliorate the disease, but a permanent cure is not yet available. In this work, we showed that human ATII cells isolated from IPF patients displayed impaired trans-differentiation in vitro. When transfected with miR-200c the ability of trans-differentiation was restored. The administration of miR-200c into mice lungs was performed using an aerosol delivery system, which resulted in an inhibited fibrosis in bleomycin-induced lung fibrosis mouse model. This data confirms miR-200c to be a powerful anti-fibrotic treatment in conditions of early onset fibrosis and when fibrosis was already established. We investigated if ATII differentiation could be rescued upon down-regulation of Flt1 a miR-200c target and highly expressed in endothelial cells. For this reason, we performed co-culture assays between endothelial cells from both Wild type (WT) and Cdh5 -ERT2-CreFlt1flox/flox mice, depleting Flt1 in endothelial cells, and ctrl and bleomycin ATII cells. We observed that the knock-out of Flt1 in endothelial cells prevented disease progression in a murine model of lung fibrosis, through releasing an increased amount of angiocrine factors, such as SerpinC1, Haptoglobin, Itih2 detected by mass spectrometry analysis of the secretome. This work importantly contributed to the discovery of a new potential IPF treatment, such as miR-200c, and to the underlying molecular mechanisms involved in both lung fibrosis and lung regeneration. Idiopathic pulmonary fibrosis (IPF) is a devastating progressive fibrotic disease affecting the lungs and causing chronic respiratory failure. In IPF, adult alveolar type II stem cells (ATII) cannot trans-differentiate to alveolar type I cells (ATI), and therefore, represents a relevant target in the progression of lung fibrosis. There are only two FDA-approved drugs for the treatment of IPF, which can only ameliorate the disease, but a permanent cure is not yet available. In this work, we showed that human ATII cells isolated from IPF patients displayed impaired trans-differentiation in vitro. When transfected with miR-200c the ability of trans-differentiation was restored. The administration of miR-200c into mice lungs was performed using an aerosol delivery system, which resulted in an inhibited fibrosis in bleomycin-induced lung fibrosis mouse model. This data confirms miR-200c to be a powerful anti-fibrotic treatment in conditions of early onset fibrosis and when fibrosis was already established. We investigated if ATII differentiation could be rescued upon down-regulation of Flt1 a miR-200c target and highly expressed in endothelial cells. For this reason, we performed co-culture assays between endothelial cells from both Wild type (WT) and Cdh5 -ERT2-CreFlt1flox/flox mice, depleting Flt1 in endothelial cells, and ctrl and bleomycin ATII cells. We observed that the knock-out of Flt1 in endothelial cells prevented disease progression in a murine model of lung fibrosis, through releasing an increased amount of angiocrine factors, such as SerpinC1, Haptoglobin, Itih2 detected by mass spectrometry analysis of the secretome. This work importantly contributed to the discovery of a new potential IPF treatment, such as miR-200c, and to the underlying molecular mechanisms involved in both lung fibrosis and lung regeneration.

ObjectiveTo describe the respiratory trajectories and their correlation with motor function in an international pediatric cohort of patients with type 2 and nonambulant type 3 spinal muscular atrophy (SMA).MethodsThis was an 8-year retrospective observational study of patients in the International SMA Consortium (iSMAc) natural history study. We retrieved anthropometrics, forced vital capacity (FVC) absolute, FVC percent predicted (FVC%P), and noninvasive ventilation (NIV) requirement. Hammersmith Functional Motor Scale (HFMS) and revised Performance of Upper Limb (RULM) scores were correlated with respiratory function. We excluded patients in interventional clinical trials and on nusinersen commercial therapy.ResultsThere were 437 patients with SMA: 348 with type 2 and 89 with nonambulant type 3. Mean age at first visit was 6.9 (±4.4) and 11.1 (±4) years. In SMA type 2, FVC%P declined by 4.2%/y from 5 to 13 years, followed by a slower decline (1.0%/y). In type 3, FVC%P declined by 6.3%/y between 8 and 13 years, followed by a slower decline (0.9%/y). Thirty-nine percent with SMA type 2% and 9% with type 3 required NIV at a median age 5.0 (1.8–16.6) and 15.1 (13.8–16.3) years. Eighty-four percent with SMA type 2% and 80% with type 3 had scoliosis; 54% and 46% required surgery, which did not significantly affect respiratory decline. FVC%P positively correlated with HFMS and RULM scores in both subtypes.ConclusionsIn SMA type 2 and nonambulant type 3, lung function declines differently, with a common leveling after age 13 years. Lung and motor function correlated in both subtypes. Our data further define the milder SMA phenotypes and provide information to benchmark the long-term efficacy of new treatments for SMA.

Omar S Usmani,1 Nicola Scichilone,2 Benjamin Mignot,3 Dennis Belmans,3 Cedric Van Holsbeke,3 Jan De Backer,3 Roberta De Maria,4 Erika Cuoghi,4 Eva Topole,4 George Georges4 1Airway Disease Section, National Heart and Lung Institute, Imperial College, London, UK; 2PROMISE Department of Medicine, University of Palermo, Palermo, Italy; 3FLUIDDA, Kontich, Belgium; 4Chiesi Farmaceutici, SpA, Parma, ItalyCorrespondence: George GeorgesChiesi USA Inc., 175 Regency Woods Place, Ste. 600, Cary, NC 27518, USATel +1 (919) 678 6611 x1536Email george.georges@chiesi.comIntroduction: There is a clear correlation between small airways dysfunction and poor clinical outcomes in patients with chronic obstructive pulmonary disease (COPD), and it is therefore important that inhalation therapy (both bronchodilator and anti-inflammatory) can deposit in the small airways. Two single-inhaler triple therapy (SITT) combinations are currently approved for the maintenance treatment of COPD: extrafine formulation beclomethasone dipropionate/formoterol fumarate/glycopyrronium bromide (BDP/FF/GB), and non-extrafine formulation fluticasone furoate/vilanterol/umeclidinium (FluF/VI/UMEC). This study evaluated the lung deposition of the inhaled corticosteroid (ICS), long-acting β2-agonist (LABA), and long-acting muscarinic antagonist (LAMA) components of these two SITTs.Materials and Methods: Lung deposition was estimated in-silico using functional respiratory imaging, a validated technique that uses aerosol delivery performance profiles, patients’ high-resolution computed tomography (HRCT) lung scans, and patient-derived inhalation profiles to simulate aerosol lung deposition.Results: HRCT scan data from 20 patients with COPD were included in these analyses, who had post-bronchodilator forced expiratory volume in 1 second (FEV1) ranging from 19.3% to 66.0% predicted. For intrathoracic deposition (as a percentage of the emitted dose), deposition of the ICS component was higher from BDP/FF/GB than FluF/VI/UMEC; the two triple therapies had similar performance for both the LABA component and the LAMA component. Peripheral deposition of all three components was higher with BDP/FF/GB than FluF/VI/UMEC. Furthermore, the ratios of central to peripheral deposition for all three components of BDP/FF/GB were < 1, indicating greater peripheral than central deposition (0.48± 0.13, 0.48± 0.13 and 0.49± 0.13 for BDP, FF and GB, respectively; 1.96± 0.84, 0.97± 0.34 and 1.20± 0.48 for FluF, VI and UMEC, respectively).Conclusions: Peripheral (small airways) deposition of all three components (ICS, LABA, and LAMA) was higher from BDP/FF/GB than from FluF/VI/UMEC, based on profiles from patients with moderate to very severe COPD. This is consistent with the extrafine formulation of BDP/FF/GB.Keywords: tomography, X-ray computed, metered dose inhalers, dry powder inhalers, inhaled corticosteroid, long-acting beta2 agonist, long-acting muscarinic antagonist

Study Objectives: Patients with chronic kidney disease (CKD) often report poor sleep quality, but they commonly exhibit OSA. The aim of this study was to evaluate the influence of OSA severity and of estimated glomerular filtration rate impairment on objective sleep quality in nondialyzed patients with CKD, defined as an estimated glomerular filtration rate, ResMed Foundation ResMed Foundation European Respiratory Society, ERS European Cooperation in Science and Technology, COST, All authors have seen and approved the manuscript. By submitting the manuscript to the journal, the authors affirm that it is an original manuscript, is unpublished work if not as an abstract, and is not under consideration elsewhere. Work for this study was performed at institutions listed in the acknowledgments. This study was funded by support for the European Sleep Apnea Database network from the European Union COST Action B26 and the European Respiratory Society–funded Clinical Research Collaboration (funding 2015–2020). Unrestricted seed grants from the ResMed Foundation and the Philips Respironics Foundation for the establishment of the database in 2007 and 2011 are gratefully acknowledged. The European Sleep Apnea Database has a scientific collaboration with Bayer AG. O.M., F.C, G.R., P.S., P.J., O.K.B., I.B., S.S., A.P., R.S., and J.V. do not have any financial interests or connections, direct or indirect, or other situations that might raise the question of bias in the work reported or the conclusions, implications, or opinions stated. J.H. reports grants from ResMed, Philips Respironics, Bayer, and the European Respiratory Society related to maintenance of the database on behalf of the European Sleep Apnea Database group. L.G. reports a collaboration between the European Sleep Apnea Database network and Bayer. M.R.B. reports research financial support by Vivisol and Medicair Italy and honoraria from ResMed and Bioproject.